Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions [1 ed.] 9781616681036, 9781604569933

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

CROHN’S DISEASE: ETIOLOGY, PATHOGENESIS AND INTERVENTIONS

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

CROHN’S DISEASE: ETIOLOGY, PATHOGENESIS AND INTERVENTIONS

JACK N. CADWALLER Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Science Publishers, Inc. New York

Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

Copyright © 2008 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Available Upon request ISBN: H%RRN 

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Contents vii 

Preface Short Communication A Enteric Glia Cells and Chronic Inflammatory Bowel Disease Georg von Boyen and Max Reinshagen 

1 

Short Communication B

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Laparoscopic-Assisted Ileocecal Resection for Crohn’s Disease: Report of Safety and Easy Technique H. Bedioui, A. Daghfous, F. Chebbi, S. Ayadi, A. Ammou W. Rebai, R. Ksantini, F. Fteriche, M. Jouini, M. Kacem, N. Ben Mami, A. Filali and Z. Ben Safta  Chapter 1

Chapter 2

9 

 

Surgery for Intestinal Crohn’s Disease and Postoperative Management for Prevention of Recurrence:Current Evidence Takayuki Yamamoto 

17 

Dendritic Cells and Intestinal Epithelial Permeability in Crohn´s Disease Manuel A. Silva 

67

Chapter 3

Monitoring Crohn´s Disease (CD) Lone G. M. Jørgensen 

101 

Chapter 4

Surgical Intervention for Small Bowel Crohn’s Disease Bobby V. M. Dasari and Keith R. Gardiner 

121 

Chapter 5

A Rasch Model of the Crohn’s Disease Activity Index (CDAI): Equivalent Levels of Ranked Attribute and Continuous Variable Scales William R. Best

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141 

vi Chapter 6

Contents The Utility of Serological Markers in Inflammatory Bowel Diseases: Gadget or Magic? Maria Papp, Gary L. Norman, Istvan Altorjay and Peter Laszlo Lakatos 

Chapter 7

Genetics of Crohn’s Disease Maria Concetta Renda and Mario Cottone 

Chapter 8

Recombinant Human Growth Hormone Treatment in Patients with Growth Deficiency and Crohn’s Disease: New Perspectives Mieczysław Szalecki, Jerzy Starzyk and Małgorzata Wójcik 

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Index

Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

171 

195 

207  227 

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Preface This new book is devoted to research on Crohn's disease (also known as regional enteritis) which is a chronic, episodic, inflammatory bowel disease (IBD) and is generally classified as an autoimmune disease. Crohn's disease can affect any part of the gastrointestinal tract from mouth to anus; as a result, the symptoms of Crohn's disease vary among afflicted individuals. The disease is characterized by areas of inflammation with areas of normal lining inbetween in a symptom known as skip lesions. The main gastrointestinal symptoms are abdominal pain, diarrhea (which may be bloody, though this may not be visible to the naked eye), constipation, vomiting, weight loss or weight gain. Crohn's disease can also cause complications outside of the gastrointestinal tract such as skin rashes, arthritis, and inflammation of the eye. Although the cause of Crohn's disease is not known, it is believed to be an autoimmune disease that is genetically linked. The highest relative risk occurs in siblings, affecting males and females equally. Smokers are three times more likely to get Crohn's disease.Unlike the other major types of IBD, there is no known drug based or surgical cure for Crohn's disease. Treatment options are restricted to controlling symptoms, putting and keeping the disease in remission and preventing relapse. Short Communication A - Enteric glia (EG) cells play an important role in the maintenance of tissue integrity in the gastrointestinal tract. Thus, genetic ablation of glial fibrillary acidic protein (GFAP) -positive EG cells in mice induced fatal hemorrhagic jejunoileitis and led to death within a few days. Furthermore transgenic mouse systems have demonstrated that ablation of EG by autoimmune T-cell targeting induces an intestinal pathology that shows similarities to the early intestinal immunopathology of Crohn’s disease. The exact mechanisms of EG to contribute to gut homeostasis remains enigmatic. Several lines of evidence implicate the secretion of neurotrophic factors and the release of SNitrosoglutathione by EG cells may be a part of the glial regulation of gut homeostasis. Both neurotrophic factors and S-Nitrosoglutathione regulate apoptosis, tight-junction integrity and cellular interactions of intestinal epithelial cells, which are necessary for the intestinal barrier. Disruption of the enteric glia cell network in patients with chronic inflammatory bowel disease may represent one possible cause for the enhanced mucosal permeability state and vascular dysfunction that are thought to favor mucosal inflammation. Short Communication B - Patients with Crohn’s disease eventually will require surgery at some stage of their disease. In fact surgery is unavoidable in 80 % of patients with ileal Crohn’s disease after 10 years of progressive disease [1, 2]. Nowadays, laparoscopic

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Jack N. Cadwaller

approach is more and more employed in colorectal field, particularly in Chronic Inflammatory Bowel Disease. The aim of this study is to demonstrate, through a single center experience, the feasibility and outcome of laparoscopic ileocecal resection. Chapter 1 - Many patients with Crohn’s disease will require surgery. Surgery is used either to relieve clinical symptoms that do not respond to medications or to correct complications such as bowel obstruction, perforation, abscess, fistula or bleeding. However, Crohn’s disease cannot be cured by surgery. In the management of jejunoileal Crohn’s disease, the most common surgical procedure is resection. For fibrotic strictures, strictureplasty is a useful surgical technique that relieves the obstructive symptoms, while preserving intestinal length and avoiding the development of short bowel syndrome. However, the role of strictureplasty in duodenal and colonic diseases remains controversial. Ileocecal disease is usually treated with resection. There is a low risk of multiple resections leading to short bowel syndrome. For localized Crohn’s colitis, segmental resection often avoids the need for a permanent stoma, and patients have good anorectal function. In the management of extensive colitis, after total colectomy with ileorectal anastomosis (IRA), the recurrence rates and functional outcomes are reasonable if the rectum is not severely affected and sphincter function is not compromised. For patients with rectal involvement, total colectomy and end-ileostomy is safe and effective; however, a few patients can have IRA, and half of the patients will require proctectomy later. Proctocolectomy is associated with a high incidence of complications, particularly delayed perineal wound healing, but it carries a low recurrence rate. Patients undergoing proctocolectomy with ileal pouch-anal anastomosis had poor functional outcomes and high failure rates. In patients with Crohn’s disease, postoperative recurrence is common. Smoking significantly increased the risk of recurrence. Quitting smoking reduced the postoperative recurrence rate. All patients should stop smoking. Mesalamine has been shown to reduce recurrence rates after surgery, albeit its efficacy is weak. Nitroimidazole antibiotics prevent early postoperative recurrence but are not well tolerated. Recent randomized trials reported that immunosuppressants reduced postoperative recurrence rates, but further clinical trials are necessary to assess their efficacies. Infliximab is the most effective medication for Crohn’s disease; however, its efficacy as a maintenance therapy after operation has not yet been reported. Enteral nutrition may help prevent recurrence, but this should be investigated in well-designed prospective studies. Endoscopic features in early postoperative period are useful for predicting future clinical relapse. Patients with severe endoscopic disease in early postoperative period are at high risk of clinical recurrence, and those patients should be treated with effective prophylactic medications. Chapter 2 - Crohn´s disease (CD) is a chronic gastrointestinal inflammatory disorder considered to be the result of an inappropriate and exaggerated mucosal immune reaction to yet undefined triggers from the gut flora. This inflammatory phenomenon has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. In the gut, mucosal DCs are separated from the luminal milieu by a monolayer of cylindrical epithelial cells which forms an anatomical and physiological barrier that control the normal traffic of antigens between both compartments.

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Preface

ix

An imbalance of colonic and ileal DC distribution in tissues from Crohn´s disease patients as well as functional differences between DCs isolated from normal and diseased intestinal samples have been demonstrated. Moreover, a gut barrier defect in the para- and transepithelial routes in addition to a significant reduction in the intestinal secretion of epithelial products involved in barrier function has been well documented in Crohn´s disease. Therefore, this may expose the diseased mucosa to overwhelming amounts of antigens resulting in abnormal DC activation and a subsequent imbalance in their distribution. In conclusion, this chapter provides a summary of relevant progress in Crohn´s disease, intestinal epithelial permeability and DCs highlighting a potential relationship between increased epithelial permeability and abnormal DC distribution during the pathogenesis of intestinal inflammation. Chapter 3 - Hospital accreditation is a recent trend in modern medicine and recommended by international standardization bodies. The aim is to obtain high clinical standardization. The analytical disciplines were some of the first to be standardised. It was based on described procedures and standards for technical equipment. WHO initiated this precision work, which was succeeded by other international organizations and recommendations from the The Joint Commission (JC), US Food and Drug Administration (FDA), European Commission (EC), International federation of clinical chemistry (IFCC), National Committee for Clinical Laboratory Standards (CLIA), or other international standardization bodies. A further step was to produce standard reference preparations or so called gold standards to attempt good validity or accuracy. This initiative has been most successful in disciplines, which are concerned with issues or variables, which can be quantitated. Recently, clinical disciplines implemented similar national quality programs according to JC to ensure different patients the same clinical procedure. Clinical procedures with patients should thus pay attention to predefined procedures, which are described and should be followed. This initiative with accreditation refers to precision in procedures and do not pay attention to assumed clinical importance or medical significance. Accurate disease diagnosis, identification of relapse vs. response to treatment, and assumed prognostic impact for clinical outcome are not included in the accreditation programs. To describe quality a certification procedure is needed and mandates gold standards. Chapter 4 - Approximately seventy percent of patients with Crohn’s disease (CD) require surgical management at some point during the course of their disease. CD commonly involves the small bowel; surgery is indicated for failure of medical therapy and complications of the disease (strictures, abscesses, fistulas, hemorrhage). Conservative strategies (strictureplasty and conservative resection) are preferred to conventional radical resection with an increasing interest in minimal access surgery and nonsurgical management (percutaneous drainage of abscesses, endoluminal dilatation of strictures, antibiotic management of microperforations). Maintenance of remission achieved by surgical intervention remains a continuing challenge. Chapter 5 - The Crohn’s Disease Activity Index (CDAI) was developed in the early 1970s using data from 112 patients with this disease at 13 university centers. Physicians’ appraisal of degree of sickness on a four-value ranked attribute scale was predicted by multiple regression through the origin using what are considered seven independent

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variables, essentially four ranked attribute, and three continuous, the former coded as if equal interval and all coded so increasing values reflected increasing disease severity. Three are seven-day sums from the patient’s diary. Coefficients were rounded to facilitate computation, and resultant CDAI values in these patients were -27 to +662. This index has since been widely used in clinical trials of Crohn’s disease. A partial credit Rasch model is developed from these patients’ data, each scale collapsed to 3-6 ranked-categories. Output of main interest is the equal-interval Rasch logit of each patient. Relationship of each of the nine component CDAI variables to Rasch logits is explored through scattergrams with jittered coincident points. Logic plus examination of these graphs indicate that best-fit scales should be smooth, monotonic, and with decreasing logit steps for equal interval variable steps. An origin-shifted logarithmic equation, encompassing observed ranges of a variable (X) and logit (Y), fits these specifications well; Y = a + b loge(X + c). An objective in this effort is to juxtapose nine component CDAI scales and a single Rasch logit scale, so a viewer may appreciate equivalencies within observed ranges. This requires that the relationship between any two variables be the same in both directions. In conventional regression they are not. The curve that best describes equivalency between two scales is that passing through the same percentile values of those scales. Percentile is calculated as p=100(3i-1)/(3n+1), where i is rank and n is total. Good fit to the origin-shifted logarithmic model is generally possible using three points, low, middle, and high. 5-50-95 percentiles were chosen for this sample, resulting in about 6 values in each tail. One cannot usually infer equal-interval relationships between values in ranked-attribute variables. However, assuming a continuous, unbounded distribution permits data manipulations not otherwise possible. A simple model used here assigns integers to categories, 0 through k, with range, -0.5 to k+0.5. Zero implies a finding absent or at normal levels. Ties at any integer level, i, are then distributed uniformly between i-0.5 and i+0.5, rendering each percentile unique. Whether this approach is credible in any case depends on the face validity of resultant formulations. An alternate approach for continuous variables is Deming regression, also producing a single relationship independent of direction. Ideally, one needs the error variance of each variable and computations are complex. However, assuming proportionate error is often intuitively appropriate and greatly simplifies computation. The 5-50-95 percentile approach produces an origin-shifted logarithmic equation for each of nine CDAI variables, whereas linear equations result from two of three continuous variables under proportionate-error Deming regression. 5-50-95 percentile appears to have greater face validity. The final illustration, juxtaposing CDAI and Rasch logit scales, clearly fulfills its objective. Chapter 6 - The panel of serologic markers for inflammatory bowel diseases (IBD) is rapidly expanding. Anti–Saccharomyces cerevisiae antibodies (ASCA) and atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) remain the most widely investigated; however there are methodological difficulties and no clear guidelines for immunofluorescence detection and interpretation of ANCA patterns in IBD hampering the diagnostic potential of the test. Increasing amount of experimental data is available on newly discovered antibodies directed against various microbial proteins and carbohydrates. Such

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antibodies include anti-OmpC (outer membrane porin C), anti-Pseudomonas fluorescens (anti-I2), anti-flagellin antibody CBir1 and antiglycan antibodies (anti-laminaribioside carbohydrate antibody [ALCA], anti-chitobioside carbohydrate antibody [ACCA], antimannobioside carbohydrate antibody [AMCA]). The pathogenic significance of these antibodies has not been established and it remains unclear whether they arise as a result of tissue damage, increased permeability or the mucosal immune perturbation seen in Crohn’s disease. Reactivity to microbial components was associated with NOD2/CARD15 genotype. Moreover, positive correlation was found between the number of mutations and the prevalence of antimicrobial antibodies (gene dosage effect), further supporting the role of altered microbial sensing in the pathogenesis of Crohn’s disease. The role of the assessment of various antibodies in the current IBD diagnostic algorithm is often questionable due to their limited sensitivity. In contrast, the association of serologic markers with disease behaviour and phenotype is becoming increasingly well-established. An increasing number of observations confirm that patients with Crohn’s disease expressing multiple serologic markers at high titers are more likely to have complicated small bowel disease (e.g. stricture and/or perforation) and are at higher risk for surgery than those without, or with low titer of antibodies (serology dosage effect). Creating homogenous disease subgroups based on serologic response may help develop more standardized therapeutic approaches and may help in a better understanding of the pathomechanism of inflammatory bowel diseases. Further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD. Chapter 7 - Strong familial aggregation, twin studies and genetic associations underline the important role of genetics in Crohn’s disease (CD). Over the past years, a combination of progress in scientific methods and in the knowledge about the human genome by genome wide association studies (GWA) has unravelled multiple genetic associations in CD. In this chapter we review the most important genetic findings in CD. Chapter 8 - About 50% of children with Crohn’s disease (CD) experience significant growth retardation, and approximately 20-25% suffer from short stature. Current guidelines concerning the use of biosynthetic growth hormone do not include patients with CD. This is probably due to the fact that the etiology of growth disturbances is not fully understood, and because there is a lack of studies regarding the effectiveness of rhGH treatment in large groups of CD patients. Growth disturbances in CD patients result from negative consequences of the diseaserelated factors, as well as from the adverse effects of the treatment. It would appear that the most important factor leading to growth retardation is chronic inflammation and excessive inflammation-related cytokine release (IL-6 and TNF-α mainly), which may cause growth hormone resistance, as the concentration of GH in these patients is normal or elevated and the concentration of insulin-like growth factor–I (IGF-I) is decreased. Adverse effects also include impaired absorption, intestinal protein loss and caloric deficit, which in effect cause an increase in the catabolic process, which is intensified by the routine application of corticotherapy. There are high hopes related to the effects of the pharmacological activity of IgG anti TNF-α monoclonal antibodies (infliximab), which reduces the inflammatory state, improves GH sensitivity, increases the concentration of IGF-I and encourages growth.

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In cases of profound growth deficiency, simultaneous treatment with rhGH – starting at the dose of 0.33 mg/kg/week – would be advised. Considering the high risk of dyslipidemia and premature osteoporosis, the metabolic effects of rhGH include a decrease of the fat to lean body mass ratio, improvement of lipid profile, bone mineralization and peak bone mass, which can be beneficial in all cases, including adults with CD. Other advantages of rhGH therapy observed in CD patients include immunomodulating and trophic effects on the bowels, resulting in the stimulation of growth, proliferation, prolonged life span and an increased collagen synthesis of the intestinal villi cells in addition to protective action against the catabolic effects of the corticosteroids. The latter effect is also used in cases of patients with juvenile idiopathic arthritis (JIA). Potentially negative effects consisting in development of insulin resistance and impaired glucose tolerance should be considered, especially as there is an excessive GH production (relative to IGF-I production) in CD and JIA patients. It seems that the use of recombinant human IGF-I in CD patients is favorable, especially as the observed beneficial effects result almost exclusively from the direct, IGF-I tissue-level impact. More prospective, multicenter studies are necessary to determine the effectiveness and safety of both treatment methods.

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In: Crohn’s Disease: Etiology, Pathogenesis and Intervention ISBN 978-1-60456-993-3 Editor: Jack N. Cadwaller © 2008 Nova Science Publishers, Inc.

Short Communication A

Enteric Glia Cells and Chronic Inflammatory Bowel Disease

1

Georg von Boyen∗1 and Max Reinshagen2 Department of Medicine I (Gastroenterology), University of Ulm 2 Department of Medicine I, Klinikum Braunschweig

Abstract

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Enteric glia (EG) cells play an important role in the maintenance of tissue integrity in the gastrointestinal tract. Thus, genetic ablation of glial fibrillary acidic protein (GFAP) -positive EG cells in mice induced fatal hemorrhagic jejuno-ileitis and led to death within a few days. Furthermore transgenic mouse systems have demonstrated that ablation of EG by autoimmune T-cell targeting induces an intestinal pathology that shows similarities to the early intestinal immunopathology of Crohn’s disease. The exact mechanisms of EG to contribute to gut homeostasis remains enigmatic. Several lines of evidence implicate the secretion of neurotrophic factors and the release of SNitrosoglutathione by EG cells may be a part of the glial regulation of gut homeostasis. Both neurotrophic factors and S-Nitrosoglutathione regulate apoptosis, tight-junction integrity and cellular interactions of intestinal epithelial cells, which are necessary for the intestinal barrier. Disruption of the enteric glia cell network in patients with chronic inflammatory bowel disease may represent one possible cause for the enhanced mucosal permeability state and vascular dysfunction that are thought to favor mucosal inflammation.

∗

Address for correspondence: Dr. Georg BT von Boyen, Department of Medicine I University of Ulm, RobertKoch-Str. 8. 89081 Ulm, Germany. Phone: +49-731-500-44603; Fax: +49-731-500-44610. E-mail: [email protected]

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2

Georg von Boyen and Max Reinshagen

Enteric Nervous System The gastrointestinal tract is characterized by an extensive and elaborate intrinsic nervous system, the enteric nervous system (ENS) [1]. It extends from the esophagus to the sphincter ani internus and includes the nervous elements within the walls of gallbladder, the cystic duct, the common bile duct and the pancreas. Due to the high number of neurons (108) and to the afore mentioned structural and functional characteristics reflecting certain parallels to the central nervous system, the ENS is called the brain of the gut [2]. Interestingly, most of the enteric neurons are not directly innervated by a preganglionic input from the brain or spinal cord. The ENS can be regarded as a fully independent part of the autonomous nervous system, which also includes the sympathetic and parasympathetic systems. Located in close proximity to intestinal effector systems the ENS controls motility [3] exocrine, endocrine and paracrine secretion [4], and it is involved in the regulation of microcirculation, absorption [5] and gut sensation [6,7]. The ENS also seems to have an effect on immune and inflammatory processes of the gut [8,9]. This modulating function during inflammatory processes appears to be mediated in parts by enteric glia (EG) cells.

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Enteric Glia (EG) Enteric glia (EG) is part of the ENS and exceedingly more abundant than neurons. Historically EG was seen as a structural supporting cell for neurons. This concept has recently been challenged. EG cells are different to Schwann cells but share morphological similarities with astrocytes in the central nervous system [10]. Both cell types are characterized by the same markers and intermediate filaments, share the resting and reactive morphology and express MHC complexes. In the ENS EG cells clear excess potassium ions and neurotransmitters from the synaptic cleft and may thereby play a role in enteric neurotransmission [11]. In addition they interact with intestinal epithelial cells and seem to be immunomodulatory [8, 9]. Thus, several lines of evidence implicate EG cells in regulating the inflammatory response of the gut, although their precise contribution to gut homeostasis remains enigmatic [9, 12]. Thus in 1998, genetic ablation of glial fibrillary acidic protein (GFAP)-positive EG in mice induced a fulminant hemorrhagic jejuno-ileitis with histopathological changes closely resembling human Crohn’s disease (CD) [13,14]. Another animal model with lymphocyte-induced reduction of GFAP-positive EG confirmed these inflammatory changes in the gut. [15]. These animals developed a severe transmural inflammation of the gut by the continuous reduction of EG cells. In comparison to human beings, the authors showed, that GFAP-positive EG seem to be reduced in patients with CD, whereas gut inflammation leads to a high increase of GFAP-positive EG [16]. Thus a defect and insufficient EG network could be postulated for patients suffering from CD [15]. The exact mechanisms of EG cells to regulate intestinal homeostasis were still unclear.

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Enteric Glia Cells and Chronic Inflammatory Bowel Disease

3

Nevertheless, the secretion of neurotrophic factors, TGFβ1 and nitric oxide metabolite Snitrosogluthatione (GSNO) might play an important role.

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Enteric Glia and Gut Homeostasis EG cells are the main source of neurotrophic factors in the gut [17-22]: Glia cells secrete glia cell-derived neurotrophic factor (GDNF) [17, 22], nerve growth factor (NGF) [19, 20], brain-derived neurotrophic factor (BDNF) (unpublished data) and transforming growth factorβ1 (TGFβ1) [21]. During gut inflammation there is a dramatically increase of GDNF and NGF in EG cells [17, 20]. Additionally an increase of GDNF in EG cells was found in the inflamed mucosa of patients suffering from inflammatory bowel disease [17, 22]. In contrast, there is nearly no GDNF in the mucosal EG of control persons [17]. GDNF released by EG do not only support the survival of the ENS neurons, they were also shown to be important for the preservation of an intact epithelial lining both, by maintaining the integrity of the bowel and promoting the regeneration after mucosal wounding [22]. Therefore, GDNF secreting EG cells may contribute to balance apoptosis and regeneration of enterocytes. This balance is thought to be crucial for maintaining an intact barrier function of the colon epithelium [23]. Increased epithelial apoptosis may lead to a leakage of the epithelial lining, which allows the translocation of luminal antigens into the mucosa, where inflammatory processes and release of proinflammatory cytokines are initiated [23,24]. This mechanism is likely to be contributing to the pathogenesis of inflammatory bowel disease. Furthermore, a protective role of the neurotrophin – NGF for gut integrity could be shown. Thus, immunodepletion of NGF or neurotrophin-3 deteriorates the inflammation during experimental colitis of the rat [25]. NGF is also highly secreted by EG cells during gut inflammation like the neurotrophic factor GDNF (20). Thus, EG seems also to be involved in regulating intestinal homeostasis by secreting NGF. Patients suffering from inflammatory bowel disease show a high increase of NGF in their intestines [19], indicating NGF-secreting EG as part of the puzzle in this disease. Recently, it was shown, that EG has the ability to synthesize and secrete TGFβ1 and leads to strong anti-proliferative effects on intestinal epithelial cells, which is partly regulated by TGFβ1 [21]. In addition an increase of the cell surface area of epithelial cells was observed in co-culturing with EG cells. The mediated factors for these phenomena are not clear. Nevertheless, both, the anti-proliferative effect and the change of epithelial cell surface, are strong evidence for EG cells as a major regulator of intestinal barrier functions and homeostasis. EG have also recently be shown to produce the nitric oxide metabolite Snitrosoglutathione (GSNO), a novel potent inducer of intestinal barrier function in transgenic mice and in human colon [26]. S-nitrosylation of protein cysteine residues functions in a manner analogous to posttranslational phosphorylation, and may drastically alter protein function [27]. In the case of GSNO-mediated regulation of epithelial barrier function, this appears in part to be influenced by altering the expression and/or S-nitrosylation of perijunctional F-actin and the association of tight-junction-associated proteins. Many complex

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biological responses of nitric oxide have recently been attributed to S-nitrosothiols, and an insufficient expression of this class of molecule contributes to inflammatory disease pathogenesis in asthma [28] and amyotrophic lateral sclerosis [29]. It is therefore reasonable that GSNO, which was found to derive from EG and to promote barrier functions in intestinal epithelia, might be involved in the pathogenesis of inflammatory bowel disease [30]. In conclusion, the glial components of the ENS could be seen as acting in concert with other components of the mucosa such as fibroblasts or dendritic cells to finely tune intestinal epithelial cell apoptosis, proliferation, migration or regulating tight-junction proteins and thus contribute to the maintenance of the intestinal barrier integrity.

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Inflammatory Bowel Disease Inflammatory bowel disease (IBD), most commonly categorized into CD and ulcerative colitis, primarily afflicts the distal small and large intestine [31]. At present, there is no definitive cure and despite extensive research, the etiology of this disease complex remains unknown. Nevertheless, it is likely, that IBD represents a common histological and clinical manifestation of several different underlying disorders. There is currently little evidence to suggest that a specific pathogenic organism is involved in the etiology of IBD. Thus, the gut microflora plays an important role in initiating and maintaining intestinal inflammation [32, 33]. Furthermore, it has been demonstrated that mutations in the NOD2/CARD15 leucine-rich repeat variants are associated with susceptibility to CD (34). Mutant NOD2/CARD15 associated with CD confers a decreased ability for monocytes to respond to bacterial lipopolysaccharide, suggesting a link between innate immune dysfunction and development of IBD. Moreover, in several experimental animal models of gut inflammation, treatment with broad-spectrum antibiotics reduces histological damage and prevents the development of chronic colitis [35]. Since intestinal commensals or toxins generally have little capacity to invade the mucosa, this further suggests that the interaction between enteric bacteria and the host immune system takes place at mucosal sites and may promoted by defects in intestinal epithelial integrity. A number of clinical studies have demonstrated an increased intestinal permeability in IBD, especially in CD patients and first degree relatives, where it has been suggested that a primary disorder of intestinal permeability constitutes an etiological factor in the pathogenesis [36, 37, 38]. Transgenic IBD models that retain a complete repertoire of immune effectors have clearly demonstrated the relative importance that loss of epithelial integrity plays in driving subsequent abnormal mucosa inflammation and neoplasia. In two transgenic mouse models, selective destruction of EG led to a significant compromised epithelial and vascular integrity within the gastrointestinal tract, resulting in a fulminating inflammation, hemorrhage and necrosis [13,15]. Importantly, the resulting pathology in both animal models initiates as a submucosal vasculitis reminiscent of that described for CD [39] and subsequently leads to disruption of the mucosal epithelial barrier and induction of a type 1 cytokine response. Pathology in these transgenic animal models occurred without any obvious detrimental effect on enteric neurons, suggesting that EG function itself plays an essential role in maintaining normal epithelial and vascular integrity

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Enteric Glia Cells and Chronic Inflammatory Bowel Disease

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in the gastrointestinal tract, and that fulminating tissue inflammation and necrosis ensue when the EG network is disrupted. A potential involvement of EG in human IBD has been suggested by a comparison of CD biopsy samples and the previously described transgenic models [13, 15]. Early pathological manifestations of CD include T-cell infiltration of myenteric plexi, enteric neuronal pathology, and vascular disturbances [39, 40, 41] Furthermore a myenteric plexitis in CD includes a high risk for developing acute flares after surgical intervention [40]. Examination of non-involved intestinal tissue from patients with CD, ulcerative colitis or histologically normal controls demonstrated that the EG network was significantly disrupted in CD, but not in ulcerative colitis [15, 17]. In addition, when comparing inflamed tissues from both groups of patients, although gliosis was evident in both ileal and colonic sites, this was much less pronounced in CD patients than in patients with ulcerative colitis. Therefore, non-involved intestinal mucosa in CD patients is associated with a significantly diminished EG network that appears to respond poorly to inflammatory signals. Nevertheless, EG are also likely to contribute to CD in other ways. A key feature of astroglia function is the blood brain barrier (BBB), which is formed by glial and endothelial cell interactions [42]. The BBB phenotype shares many similarities with differentiated intestinal epithelial cells, and EG secrete the same such as a high transcellular soluble mediators like astroglia (TGFβ1, GDNF, NGF and endothelins) [43]. Thus, besides BBB, a glia-epithelial barrier in the gut could be postulated. Independent observations made in EG-depleted animals have demonstrated that these cells are important regulators of gastrointestinal homeostasis, possibly by directly regulating mucosal inflammation and permeability. Similar abnormalities exist in the ileum and colon of patients with CD prior to the onset of mucosal inflammation. Because EG processes are abundant within the mucosa, soluble mediators (GDNF, NGF, TGFβ1, GSNO) may readily diffuse to interact with epithelial cells to regulate mucosal permeability. One may therefore hypothesize that a diminished or insufficient EG network that is evident prior to mucosal inflammation in CD patients may represent one possible primary cause for the enhanced mucosal permeability that is characteristic of this syndrome. This enhanced permeability may subsequently drive abnormal mucosal immune reactions to food antigens and to components of the gut microflora, which lead to the development of inflammatory bowel disease.

References [1] [2]

[3] [4]

Furness JB, Costa M. The enteric nervous system. New York: Churchill Livingstone, 1987. Gershon MD, Kirchgessner AL, Wade PR. Functional anatomy of the enteric nervous system. In: Johnson LR, ed. Physiology of the gastrointestinal tract. New York: Raven Press, 1994: 381-422. Costa M, Brookes SJ. The enteric nervous system. Am. J. Gastroenterol. 1994; 89: Suppl: S129-37. Cooke HJ. Neuroimmune signaling in regulation of intestinal ion transport. Am. J. Physiol. 1994; 266: G167-78.

Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

6 [5] [6]

[7] [8] [9]

[10] [11] [12]

[13] [14]

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

[15]

[16]

[17]

[18]

[19]

[20]

[21]

Georg von Boyen and Max Reinshagen Surprenant A. Control of the gastrointestinal tract by enteric neurons. Annu. Rev. Physiol. 1994; 56: 117-40. Grundy D, Scratcherd T. Sensory afferents from the gastrointestinal tract. In: Schulz SG, Wood JD, Rauner BB, eds. Handbook of Physiology. New York, Oxford: University Press, 1989, Vol 1: 593-620. Furness JB, Kunze WA, Clerc N. Nutrient tasting and signaling mechanisms in the gut. II. The intstines as a sensory organ: neural, endocrine, and immune. Downing JE, Mijan JA. Neural immunoregulation: emerging roles for nerves in immune homeostasis and disease. Immunol. Today. 2000; 21: 281-9. von Boyen GB, Reinshagen M, Steinkamp M et al. Gut inflammation modulated by the enteric nervous system and neurotrophic factors. Scand. J. Gastroenterol. 2002; 37: 621-625 Jessen KR, Mirsky R. Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 1980; 286: 736-737. Rühl A, Nasser Y, Sharkey KA. Enteric glia. Neurogastroenterol. Motil. 2004;16:449. von Boyen GB, Reinshagen M, Steinkamp M et al. Enteric nervous plasticity and development: dependence on neurotrophic factors. J. Gastroenterol. 2002; 37: 583588. Bush TG, Savidge TC, Freeman TC et al.. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 1998; 93: 189-201. Bush TG. Enteric glial cells. An upstream target for induction of necrotizing enterocolitis and Crohn's disease? Bioessays 2002; 24: 130-140. Cornet A, Savidge TC, Cabarrocas J et al. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease? Proc. Natl. Acad. Sci. USA 2001; 98: 13306-13311. von Boyen GB, Steinkamp M, Reinshagen M et al. Proinflammatory cytokines increase glial fibrillary acidic protein expression in enteric glia. Gut 2004; 53: 222228. von Boyen GB, Steinkamp M, Geerling I et al. Proinflammatory Cytokines Induce Neurotrophic Factor Expression in Enteric Glia: A Key to the Regulation of Epithelial Apoptosis in Crohn's Disease. Inflamm. Bowel. Dis. 2006; 24: 346-354. Bar KJ, Facer P, Williams NS et al. Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease. Gastroenterology 1997; 112: 13811385. di Mola FF, Friess H, Zhu ZW et al. Nerve growth factor and Trk high affinity receptor (TrkA) gene expression in inflammatory bowel disease. Gut 2000; 46: 670679. von Boyen GB, Steinkamp M, Reinshagen M et al. Nerve Growth Factor (NGF) secretion in cultured enteric glia cells is modulated by proinflammatory cytokines. J. Neuroendocrinol. 18:820-5. Neunlist M, Aubert P, Bonnaud S et al. Enteric Glia Inhibits Intestinal Epithelial Cell Proliferation Partly Through A Tgf-{Beta}1-Dependent Pathway. Am. J. Physiol. Gastrointest Liver Physiol. 2007;292:G231-41.

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Enteric Glia Cells and Chronic Inflammatory Bowel Disease [22]

[23] [24]

[25] [26]

[27] [28] [29] [30] [31] [32]

Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved.

[33] [34] [35] [36] [37] [38] [39] [40]

[41]

7

Steinkamp M, Geerling I, Seufferlein T et al. Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells. Gastroenterology 2003; 124: 17481757. Shanahan F. Crohn’s disease. Lancet 2002; 359: 62-69. Strater J, Wellisch I, Riedl S et al. CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology 1997; 113: 160167. Reinshagen M, Rohm H, Steinkamp M et al. Protective role of neurotrophins in experimental inflammation of the rat gut. Gastroenterology 2000; 119: 368-376. Savidge TC, Newman P, Pothoulakis C et al. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 2007;132:1344-58. Stamler JS, Toone EJ, Lipton SA et al. SNO signals: translocation, regulation, and a Consensus Motif. Neuron 1997; 18: 691-696. Que LG, Liu L, Yan Y, et al. Potection from experimental asthma by an endogenous bronchodilator. Science 2005; 308: 1618-1621. Schonhoff CM, Matsuoka M, Tummala H et al. S-nitrosothiol depletion in amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 2006; 103: 2404-2409. Savidge TC, Sofroniew MV, Neunlist M. Starring roles for astroglia in barrier pathologies of gut and brain. Lab. Invest. 2007;87:731-6. Desreumaux P, Brandt E, Gambiez L, et al. Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 1997; 113: 118-126. Elson C, Sartor RB, Tennyson GS, et al. Experimental models of inflammatory bowel disease. Gastroenterology 1995; 109: 1344-1367. French N, Petterson S. Microbe-host interactions in the alimentary tract: the gateway to understanding inflammatory bowel disease. Gut 2000; 47: 162-163. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411: 599-603. Sadlack B, Merz H, Schorle H et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253-61. Ma TY. Intestinal epithelial barrier dysfunction in Crohn's disease. Proc. Soc. Exp. Biol. Med. 1997;214:318-27. Soderholm JD, Peterson K, Olaison G, et al. Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease? Gastroenterology 1999;117:65-72. Cabarrocas J, Savidge TC, Liblau RS. Role of enteric glial cells in inflammatory bowel disease. Glia. 2003;41:81-93. Wakefield AJ, Sankey EA, Dhillon AP, et al. Granulomatous vasculitis in Crohn's disease. Gastroenterology 1991; 100:1279-87. Ferrante M, de Hertogh G, Hlavaty T, et al. The value of myenteric plexitis to predict early postoperative Crohn's disease recurrence. Gastroenterology. 2006;130:1595606. Geboes K, Collins S. Structural abnormalities of the nervous system in Crohn's disease and ulcerative colitis. Neurogastroenterol. Motil. 1998;10:189-202.

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8 [42]

Gloor SM, Wachtel M, Bollinger MF, et al. Molecular and cellular permeability control at the blood-brain barrier. Brain Res. Brain Res. Rev. 2001;36:258-64. von Boyen G, Steinkamp M. The enteric glia and neurotrophic factors. Z. Gastroenterol. 2006;44:985-90.

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[43]

Georg von Boyen and Max Reinshagen

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In: Crohn’s Disease: Etiology, Pathogenesis and Intervention ISBN 978-1-60456-993-3 Editor: Jack N. Cadwaller © 2008 Nova Science Publishers, Inc.

Short Communication B

Laparoscopic-Assisted Ileocecal Resection for Crohn’s Disease: Report of Safety and Easy Technique H. Bedioui∗1, A. Daghfous1, F. Chebbi1, S. Ayadi1, A. Ammous1 W. Rebai1, R. Ksantini1, F. Fteriche1, M. Jouini1, M. Kacem1, N. Ben Mami2, A. Filali3 and Z. Ben Safta1 1

Surgical department “A”, Rabta Hospital, Tunis, Tunisia Department of Gastroenterology “B”, Rabta Hospital, Tunis, Tunisia 3 Department of Gastroenterology “A”, Rabta Hospital, Tunis, Tunisia

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2

Abstract Background The aim of our study is to demonstrate the safety and feasibility of laparoscopic assisted ileocecal resection for Crohn’s disease, and to present our preliminary results.

Material and methods From November 2003 to June 2005, we analysed prospectively the outcome of 29 laparoscopic ileocecal resections for Crohn’s disease. In order to select the candidates for laparoscopic approach, exclusion and inclusion criteria had been clearly defined at the beginning of our study. Concerning the surgical procedure, the first time consisted of a laparoscopic mobilisation of the ileum and right colon. The key landmark for this approach was the opening of the root of mesentery at the level of the ileocecal junction. Then the dissection was led up to the duodenum and the mobilization of the ileocecum

∗

Corresponding author: MD Bedioui Heykal, Service de Chirurgie A, Hopital La Rabta, Tunis, Tunisia Mail : [email protected], Phone : 00216 98348065 Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

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was facilitated by the opening of the Told fascia. The second time is a transverse laparotomy at the level of the iliac fossa of less than 5 centimeters in diameter. The ileocecal specimen is then exteriorized. The proximal and distal bowel trans-section, vessels sealing and anastomosis were performed extracorporeally.

Results Among 41 cases of Crohn’s disease enrolled in this period, only 29 patients were included in our study. The mean operating time was 163 minutes (120-210). Conversion was needed in five cases. There is no mortality and out of 29 cases the recovery was uneventful in 26 cases. In three cases surgical site infections were detected. The mean hospital stay was 6 days (4-8 days).

Conclusion Our results have shown the feasibility and safety of laparoscopic ileocecal resection for Crohn’s disease. This approach gives superior outcome over open surgery though it needs high selection of cases, especially at the beginning of experience.

Keywords: Crohn’s disease; laparoscopy; surgery; procedure; safety.

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Introduction Patients with Crohn’s disease eventually will require surgery at some stage of their disease. In fact surgery is unavoidable in 80 % of patients with ileal Crohn’s disease after 10 years of progressive disease [1, 2]. Nowadays, laparoscopic approach is more and more employed in colorectal field, particularly in Chronic Inflammatory Bowel Disease. The aim of this study is to demonstrate, through a single center experience, the feasibility and outcome of laparoscopic ileocecal resection.

Materials and Methods All laparoscopic ileocecal resection performed between November 2003 and June 2005 in our department were prospectively recorded in a computerized database. We excluded all surgical emergency as peritonitis and obstruction, fistulizing disease (entero-urinary fistula, entero-cutaneous fistula and enter-colic fistula), phlegmons, abdominal mass > 5 cm, multiple jejuno-ileal stenosis and patients with previous laparotomy. The laparoscopic ileocecal resection is considered to be converted to an open procedure if any unplanned incision is performed larger than planned (more than 5 cm). For all our patients, the collected data was composed of: demographics (age, sex, body mass index), American Association of

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Anesthesia (ASA) score, preoperative radiographic studies, reason and time to conversion, length of procedure, length of hospital stay, morbidity, and mortality.

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Surgical Procedure Under general anesthesia patient was put in a supine position. A nasogastric tube and a urinary catheter were used systematically. The lower limbs were abducted. Trendelenburg position with 20 to 30 degrees left tilting was needed. The surgeon stood between legs and the laparoscopic tower was put in the right side at the head of the patient. The first time is a laparoscopic mobilization of the ileum and the right colon. The pneumoperitoneum was established using Veress needle inserted in the left hypochondrium. Two ten mm trocars were used; the first one was inserted in the left para-umbilical region and the second one in the suprapubic region. These two trocars will be used as camera port according to the step of intervention. Two other 5 mm trocars were also needed, one of them is placed laterally in the right flanc and the second one is placed in the left iliac fossa. A 0 degree camera was used. We proceeded with meticulous exploration of the abdominal cavity and small bowel. Then we started the colon dissection, applying medial to lateral approach. The key landmark for this approach was the opening of the root of mesentery at the level of the ileocecal junction. The dissection is safely and easy because it is led in an avascular plan. The dissection is led far from the sclerolipomatosis at the back of that plan. The areolar plane between the mesocolon and the retroperitoneum is thus exposed and developed for several centimeters. The duodenum should appear in the retroperitoneum just under the elevated ileocolic pedicle. The dissection was first carried out laterally toward the abdominal wall by opening the Told fascia and then continued superiorly under the transverse mesocolon, over the duodenum and the head of the pancreas. This dissection allows an adequate mobilization of the ileum and right colon. The second time is a transverse laparotomy at the level of the iliac fossa of less than 5 centimeters in diameter. The ileocecal specimen is then exteriorized. The proximal and distal bowel trans-section, vessels sealing and anastomosis were performed extracorporeally. Finally, the bowel was reintegrated into the abdomen and drainage was systematically placed.

Results According to above mentioned criteria of selection, among 41 cases of Crohn’s disease enrolled in this period, only 29 patients were included in our study. The reasons of exclusion were: · · · ·

recurrent disease in two cases a large abdominal mass more than 5 cm in two cases ileocolic fistula in two cases a perforating Crohn’s disease with peritonitis in three cases

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H. Bedioui, A. Daghfous, F. Chebbi et al.

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Crohn’s disease involving the entire colon in two cases A previous laparotomy in one case.

There were 18 females and 11 males with a mean age of 28 years (range between 16 and 50). The mean time elapsed from first diagnosis until surgery is needed was 31 months (2 months to 14 years). The diagnosis of Crohn’s disease was established preoperatively in 21 cases using endoscopic biopsy. In the remaining 8 cases the diagnosis was highly suspected on clinical basis, and morphological appearance. An abdominal mass was detected in 8 cases. In all these cases the size of the mass was less than 5 cm. All our patients have undergone colonoscopy and barium swallow follow-through. Solitary involvement of the ileum was found in 19 cases and a concomitant involvement of the ileum and the cecum was found in 10 cases. In 10 patients presented with fever and abdominal pain abdominal CT scan was performed. This allowed us to detect collections in two patients (4 and 6 cm) which treated percutaneously. These two patients became eligible for elective surgery three weeks later. During the intervention, solitary ileal involvement was detected in 19 cases and concomitant ileocecal involvement in ten cases. That was in concord with preoperative findings. Small abscess in the right iliac fossa was detected in three patients requiring drainage and meticulous cleaning. That allowed immediate anastomosis in all the 3 cases. A fistulizing crohn was encountered in three patients. One patient with entero-cutaneous fistula, one cases with ileo-colic fistula in and the third one with ileo-ileal fistula. The reasons for conversion were:

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· · ·

Ileocolic fistula in three cases Extended disease involving 2 metres of the small bowel in one case Difficulty to dissect in the presence of an inflammatory mass in one case.

The mean operating time was 163 minutes (120-210). None of our patients required blood transfusion. Out of 29 cases the recovery was uneventful in 26 cases. In three cases wound infections were detected. The mean postoperative hospital stay was about 6 days (4-8 days).

Discussion Surgery is an important component of Crohn’s disease management. Many studies have proved that patients with Crohn’s disease will require surgery at some point of their illness. The most commonly affected site is the terminal ileum and cecum. Within the first ten years post first attack, up to 75% of patients with ileocecal disease will require resection [2], and due to recurrence, 25 to 65 % of those who had the first resection, another resection will be needed [3]. Most of patients suffering from Crohn’s disease are young and female patients with psychological background, and those are paying great attention to cosmetic outcome. Surgery with minimum scares would greatly serve this concept. Therefore, the theoretical benefits of laparoscopy, such as improved cosmetic results, minimal pain and early return to full activity

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Laparoscopic-Assisted Ileocecal Resection for Crohn’s Disease

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with easier abdominal access when redo surgery is required could be very attractive for both, surgeons and patients. Several reports have shown that laparoscopic ileocolic resection is feasible, safe and even superior to open approach [4, 5, 6]. Milsom [4], in a prospective randomized study has reported less respiratory complications in the laparoscopic than open group with significant statistical difference. Other authors [5, 6], have reported less use of analgesics, faster recovery and reduction in the cost within the laparoscopic group though not statistically significant. Surgical technique is standardized; however some individual techniques have been reported. Regarding the number of trocars; some authors advocate the use of three trocars [5]; others prefer to use four trocars. In fact, we believe that using the fourth trocar makes the dissection easier and reduces operating time. Concerning the colon dissection, and the preference between medial to lateral, and lateral to medial approaches [7], we prefer medial to lateral approach beginning by opening the mesenteric root. With this approach we achieve a good mobilisation of the ileocolon by blunt dissection keeping away from the ileocecal junction, which is more often containing important inflammatory reaction and sclerolipomatosis. Concerning vascular sealing, some authors prefer doing this intracorporeally [7] while many others prefer to do it extracorporeally [8]. Concerning bowel resection and anastomosis, mechanical intracorporeal resection and anastomosis gives no advantage over extracorporeal mechanical or hand sewn anastomosis, neither in terms of incisional length, which is correlated with the size of the inflammatory mass, nor duration of pneumoperitoneum [7]. Another important point should be highlighted, that palpitation of the whole length of the small bowel is one of the key steps in surgery of Crohn’s disease. Consequently, as tactile sensation is lost in laparoscopy, there may be a high chance of missing strictures, and the surgeon will leave the operating room with incomplete inventory [12]. On the other hand some authors are advocating that all the procedure can be accomplished laparoscopically with great satisfaction. According to them: the absence of strictures is confirmed by not only thorough preoperative investigations, but also by “running” the whole length of the small bowel from the duodeno-jejunal flexure with two atraumatic graspers [13] and by inserting a balloon catheter through the cut ends of the bowel [14]. Finally not to forget the high cost of the procedure if we use mechanical suture and for this reason, in our practice we prefer to use manual suturing and continue to advocate that extracorporeal trans-section and anastomosis as costeffective. Our conversion rate is 17 %. This is comparable to those reported in the literature [3, 4, 5, 6]. The reasons for conversion were ileocolic fistula in three patients, extended disease involving 2 metres of the small bowel in one patient and difficult dissection of an inflammatory mass in one patient. The most important predictive factors for conversion reported in the literature were long standing disease, large mass exceeding 5 cm, recurrence, pericolic collections, and other complications of inflammation such as phlegmons and fistulas [9, 10]. Other authors concluded that tobacco, steroid administration, colonic involvement and preoperative malnutrition were predictive factors for conversion in patients undergoing surgery for Crohn’s disease [10].

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H. Bedioui, A. Daghfous, F. Chebbi et al.

In the most important series published, there is no mortality [4, 6]. In fact Crohn’s disease affects young patients without major risk factors. However morbidity is faint varying in the literature between 0 and 16 %. The most frequent complications are anastomotic leakage [4, 9], infected pelvic haematoma [9, 10, 12], postoperative ileus [4, 12, 15] and surgical site infections [4, 9, 15]. In our series, wound infection was the only complication recorded. This problem was due to inadequate wound protection during specimen exteriorization at the beginning of our experience. Milson [4] in his study has reported less complications in the laparoscopic group 16 % vs 31 % in the open surgery group. However there was no statistical significant difference. The mean length of hospital stay reported in the literature ranges between 4 and 8 days [4, 6]. In our study this was 6 days with extremes of 4 and 8 days.

Conclusion Laparoscopic surgery for ileocecal Crohn’s disease represent an attractive approach offering valid advantages when compared to open surgery. This approach could be more valuable in young patients looking after a good cosmetic result and much more exposed to recurrence and re-do resection. Nowadays its feasibility and its safety are certain at least in elective cases.

References

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[1] [2] [3] [4]

[5] [6] [7] [8]

Crohn B.B, Ginzburg L, Oppenheimer G.D. Regional ileitis: a pathologic and clinical entity. JAMA 1932; 99: 1233-1239. Andrews H.A, Keighley M.R.B, Alexander-Williams J, Allan R.N. Strategy for management of distal ileal Crohn’s disease. Br. J. Surg. 1991; 78: 679-682. Williams J.G, Wong W.D, Rothenberg D.A, Goldberg S.M. Recurrence of Crohn’s disease after resection. Br. J. Surg. 1981; 78: 10-19. Milsom JW, Hammerhofer KA, Bohm B, Marcello P, Elson P, Fazio VW. Prospective, randomized trial comparing laparoscopic vs conventional surgery for refractory ileocolic Crohn’s disease. Dis. Colon. Rectum. 2001; 44 (1): 1-8. Shore G, Gonzalez QH, Bondora A, Vickers SM. Laparoscopic vs conventional ileocolectomy for primary Crohn’s disease. Arch. Surg. 2003; 138 (1): 76-9. Hasegawa H, Watanabe M, Nishibori H, Okabayashi K, Hibi T, Kitajima M. Laparoscopic surgery for recurrent Crohn’s disease. Br. J. Surg. 2003; 90 (8): 970-3. Dutta S, Rothenberg S.S, Chang J, Bealer J. Total intracorporeal laparoscopic resection of Crohn’s disease. J. Pediatr. Surg. 2003; 38: 717-719. Von Allmen D, Markowitz JE, York A, Mamula P, Shepanski M, Baldassano R. Laparoscopic-assisted bowel resection offers advantages over open surgery for treatment of segmental Crohn’s disease in children. J. Pediatr. Surg. 2003; 38: 963-5.

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Laparoscopic-Assisted Ileocecal Resection for Crohn’s Disease [9] [10]

[11] [12] [13] [14]

Moorthy K, Shaul T, Foley RJ. Factors that predict conversion in patients undergoing surgery for Crohn’s disease. Am. J. Surg. 2004; 187: 47-51. Schmidt CM, Talamini MA, Kaufman HS, Lilliemoe KD, Learn P, Bayless T. Laparoscopic surgery for Crohn’s disease: reasons for conversion. Ann. Surg. 2001; 233 (6): 733-9. Hamel CT, Pikarsky AJ, Wexner SD. Laparoscopically assisted hemicolectomy for Crohn’s disease: are we still getting better?. Am. Surg. 2002; 68: 83-6. Gambiez L, Denimal F, Jafari-Manjili M, Kosydar P. Laparoscopic ileo-colic resection in Crohn's disease. Ann. Chir. 1999; 53 : 1039-43. Reissman P, Salky B, Pfeifer J, et al. Laparoscopic surgery in the management of inflammatory bowel disease. Am. J. Surg. 1996;171: 47–51. Mortensen N. Surgery for Crohn’s disease of the small intestine. In: Morris PJ, Malt RA, editors. Oxford textbook of surgery. Oxford: Oxford University Press, 1995, p. 973–9. Albaz O, Iroatulam A.J.N, Nessim A, Weiss E.G, Nogueras J.J, Wexner S.D. Comparison of laparoscopcally assisted and conventional ileocolic resection for Crohn’s disease. Eur. J. Surg. 2000; 166: 213-217.

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[15]

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Copyright © 2008. Nova Science Publishers, Incorporated. All rights reserved. Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

In: Crohn’s Disease: Etiology, Pathogenesis and Intervention ISBN 978-1-60456-993-3 Editor: Jack N. Cadwaller © 2008 Nova Science Publishers, Inc.

Chapter 1

Surgery for Intestinal Crohn’s Disease and Postoperative Management for Prevention of Recurrence: Current Evidence Takayuki Yamamoto∗ Inflammatory Bowel Disease Center and Department of Surgery, Yokkaichi Social Insurance Hospital, Yokkaichi, Mie, Japan

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Many patients with Crohn’s disease will require surgery. Surgery is used either to relieve clinical symptoms that do not respond to medications or to correct complications such as bowel obstruction, perforation, abscess, fistula or bleeding. However, Crohn’s disease cannot be cured by surgery. In the management of jejunoileal Crohn’s disease, the most common surgical procedure is resection. For fibrotic strictures, strictureplasty is a useful surgical technique that relieves the obstructive symptoms, while preserving intestinal length and avoiding the development of short bowel syndrome. However, the role of strictureplasty in duodenal and colonic diseases remains controversial. Ileocecal disease is usually treated with resection. There is a low risk of multiple resections leading to short bowel syndrome. For localized Crohn’s colitis, segmental resection often avoids the need for a permanent stoma, and patients have good anorectal function. In the management of extensive colitis, after total colectomy with ileorectal anastomosis (IRA), the recurrence rates and functional outcomes are reasonable if the rectum is not severely affected and sphincter function is not compromised. For patients with rectal involvement, total colectomy and end-ileostomy is safe and effective; however, a few patients can have IRA, and half of the patients will require proctectomy later. Proctocolectomy is ∗

Correspondence address: Takayuki Yamamoto, MD, PhD, FACG, Inflammatory Bowel Disease Center and Department of Surgery, Yokkaichi Social Insurance Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie 510-0016, Japan. TEL: +81 59 331 2000, FAX: +81 59 331 0354 E-mail: [email protected]

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Takayuki Yamamoto associated with a high incidence of complications, particularly delayed perineal wound healing, but it carries a low recurrence rate. Patients undergoing proctocolectomy with ileal pouch-anal anastomosis had poor functional outcomes and high failure rates. In patients with Crohn’s disease, postoperative recurrence is common. Smoking significantly increased the risk of recurrence. Quitting smoking reduced the postoperative recurrence rate. All patients should stop smoking. Mesalamine has been shown to reduce recurrence rates after surgery, albeit its efficacy is weak. Nitroimidazole antibiotics prevent early postoperative recurrence but are not well tolerated. Recent randomized trials reported that immunosuppressants reduced postoperative recurrence rates, but further clinical trials are necessary to assess their efficacies. Infliximab is the most effective medication for Crohn’s disease; however, its efficacy as a maintenance therapy after operation has not yet been reported. Enteral nutrition may help prevent recurrence, but this should be investigated in well-designed prospective studies. Endoscopic features in early postoperative period are useful for predicting future clinical relapse. Patients with severe endoscopic disease in early postoperative period are at high risk of clinical recurrence, and those patients should be treated with effective prophylactic medications.

Keywords: Crohn’s disease; stricture; abscess; fistula; gastroduodenal disease; Jejunoileal disease; Ileal disease; Ileocolonic disease; Colorecal disease; surgery; resection; bypass; strictureplasty; stoma; complications; recurrence; reoperation.

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Introduction Crohn’s disease is a chronic inflammatory disease of unknown etiology. The condition usually affects the small bowel and/or colon, but can occur in any part of the gastrointestinal tract, from the mouth to the anus. Most patients with Crohn’s disease are first treated with medications. Medical treatment can help control the symptoms and complications of disease, and may delay the need for surgery. Because there is a risk for postoperative complications and recurrence, surgery may not be appropriate for every patient with symptoms. Patients considering surgery should carefully weigh its benefits and risks compared with other treatments. Patients faced with this decision should get as much information as possible from doctors, nurses and other patients. Two-thirds to three-quarters of patients with Crohn’s disease eventually undergo surgery as part of the therapeutic management of their disease [1-3]. Since new biological agents such as infliximab are currently approved for use in patients with Crohn’s disease [4-7], the need for surgery may have diminished and the indication for surgery may have changed. But the influence of these new drugs on surgical treatment in Crohn’s disease has not yet been reported.

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Indications for Surgery Unlike ulcerative colitis, Crohn’s disease cannot be cured with surgery. Even if the diseased part of the intestine is removed, the inflammation can reappear in a previously unaffected portion of the intestine because microscopic foci of inflammation are common on grossly normal mucosa in Crohn’s disease. The primary goals of surgery are to alleviate serious complications, achieve the best possible quality of life, and conserve as much bowel as possible. Indications for surgery in Crohn’s disease include:

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Failure of medical treatment Serious adverse drug events or steroid dependency Bowel obstruction Perforation of the intestine Formation of a fistula or abscess Excessive intestinal bleeding Toxic megacolon Carcinoma Extraintestinal manifestations Growth retardation

Michelassi et al [1] reported that among 639 patients undergoing surgery for Crohn’s disease, the most common indication for surgery was failure of medical treatment (33%) followed by presence of a fistula (24%) and bowel obstruction (22%). Many patients with Crohn’s disease require surgery because of failure of medical treatment, bowel obstruction, formation of a fistula or abscess, or combination of these indications. The majority of patients with Crohn’s disease can be treated with elective surgery. However, patients with bowel perforation, peritonitis, excessive bleeding or acute obstruction require urgent surgery. A recent study analyzed changes in surgery for Crohn’s disease over a period of 33 years between 1970 and 2002, in which the rates of elective surgery compared to urgent or emergency surgery increased with time; 69.5% between 1970 and 1980, 81.4% between 1981 and 1991 and 80.9% between 1992 and 2002 [8]. Improved medical treatment may have lead to higher rates of elective operations in the management of Crohn’s disease.

Surgical Options There are various options available in the surgical management of Crohn’s disease: ƒ ƒ ƒ ƒ ƒ ƒ

Resection Bypass Strictureplasty Stoma construction Correction of fistulas Drainage of abscesses

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Takayuki Yamamoto

The aim of surgery for Crohn’s disease has shifted from radical operation, achieving inflammation-free margins of resection, to minimal surgery, intended to remove just grossly inflamed tissue or performing strictureplasty. The surgeon must assess which procedure is most suitable at each area of the disease. For example, strictures can be resected, bypassed or widened by strictureplasty.

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1. Resection When Crohn’s disease was first recognized widely, radical resection of the diseased bowel was preferred surgical option [9]. Morbidity and mortality rates after such operations were high. Thereafter, several studies found that postoperative recurrence was unaffected by the width of the margin of resection and by microscopic disease at the resection margins [1012]. There has been an increasing tendency toward minimal surgery, and strictureplasty is now widely used. However, resection is still the most common surgical procedure in the management of Crohn’s disease, and can be used for diseased bowel in most situations such as strictures, perforation, fistula, abscess or intestinal bleeding. At the present time, short strictures without perforating disease (perforation, fistula or abscess) tend to be treated with strictureplasty rather than resection. Long strictures have traditionally been treated with resection rather than strictureplasty. However, in several institutions, long strictures are also treated with new types of strictureplasties [13-19]. Since there is no evidence that resection of enlarged lymph nodes influences postoperative recurrence rates, a radical lymphadenectomy is not necessary. However, infected lymph node forming a large mass in close to a planned anastomotic line should be removed if extending resection margins is unnecessary. Following bowel resection, an anastomosis is fashioned using either hand-sewn or stapled techniques. The stapled functional end-to-end anastomosis has become a popular procedure in colorectal surgery for benign and malignant diseases [20-24]. Its potential advantages are a wide anastomotic lumen, minimal contamination and a quick method. Comparisons of outcomes after handsewn and stapled anastomoses are shown later in this article. When patients are at a high risk of anastomotic complications due to severe intraabdominal sepsis, malnutrition and long-term high dose steroid use, anastomosis is protected by a temporary stoma (e.g., loop ileostomy after ileocolonic resection with anastomosis) or anastomosis is avoided (e.g., end ileostomy and closure of ascending colon stump after ileocecal resection).

2. Bypass There were significant morbidity and mortality after radical resection for Crohn’s disease in the 1930s. Many surgeons then considered that a more conservative approach was necessary. Consequently, resection was replaced by bypass operations [25]. There are two types of bypass operations: exclusion bypass and continuity (simple) bypass. For certain types of ileocecal Crohn’s disease with associated with serious abscess or phlegmon densely adherent to the retroperitoneum, the proximal cut end of the transected ileum is anastomosed

Crohn's Disease: Etiology, Pathogenesis and Interventions : Etiology, Pathogenesis and Interventions, Nova Science Publishers, Incorporated, 2008.

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to the transverse colon in an end-to-side fashion with/without construction of a mucus fistula of the distal cut end of the ileum (exclusion bypass) or an ileotransverse colonic anastomosis is made in a side-to-side fashion (simple bypass). Several authors reported that the recurrence rate was higher after bypass operation than after resection [26]. Furthermore, bypass surgery for ileal disease was associated with persistent sepsis or fistula, and serious metabolic sequelae [26]. The most serious problem was the high incidence of malignancy in bypassed segments [27,28]. At present, bypass surgery is rarely performed for Crohn’s disease in our institution.

3. Strictureplasty In the 1980s, strictureplasy was proposed by Lee from Oxford [10] and AlexanderWilliams from Birmingham [11]. The rationale of strictureplasty is that it increases the diameter of the bowel, and relieves the obstruction without sacrificing any small bowel. Simple relief of the stricture is sufficient for improvement of clinical condition. Many authors reported that strictureplasty is safe and useful in the management of small bowel Crohn’s disease [29-35]. Nowadays, strictureplasty has become an established surgical procedure for obstructive Crohn’s disease [36]. Strictureplasty is not suitable for all patients. Indications for strictureplasty are:

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Diffuse involvement of the small bowel with multiple strictures Duodenal strictures Ileocolonic or ileorectal anastomotic strictures Stricture(s) in patients who have undergone extensive resection(s) or multiple resections of the small bowel

One of the risks of repeated or extensive resections for small bowel Crohn’s disease is the development of short bowel syndrome. Strictureplasty is most useful for patients with extensive disease with fibrotic strictures who may have undergone previous resections and are susceptible to the short bowel syndrome. In contrast, contraindications to strictureplasty are: ƒ ƒ ƒ ƒ ƒ ƒ ƒ

Perforation of the intestine Fistula or abscess formation at the intended strictureplasty site Excessive tension at strictureplasty closure due to rigid and thickened bowel segments Multiple strictures within a short segment Hemorrhagic strictures Malnutrition or hypoalbuminemia (